Coxsackievirus B Type 4 Infection in β Cells Downregulates the Chaperone Prefoldin URI to Induce a MODY4-like Diabetes via Pdx1 Silencing.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 101766894 Publication Model: eCollection Cited Medium: Internet ISSN: 2666-3791 (Electronic) Linking ISSN: 26663791 NLM ISO Abbreviation: Cell Rep Med
    • Publication Information:
      Original Publication: [Cambridge, MA] : Cell Press, [2020]-
    • Subject Terms:
      Capsid Proteins/*genetics ; Coxsackievirus Infections/*genetics ; DNA (Cytosine-5-)-Methyltransferase 1/*genetics ; Diabetes Mellitus, Type 2/*genetics ; Enterovirus B, Human/*genetics ; Homeodomain Proteins/*genetics ; Repressor Proteins/*genetics ; Trans-Activators/*genetics; Animals ; Capsid Proteins/metabolism ; Coxsackievirus Infections/metabolism ; Coxsackievirus Infections/pathology ; Coxsackievirus Infections/virology ; DNA (Cytosine-5-)-Methyltransferase 1/antagonists & inhibitors ; DNA (Cytosine-5-)-Methyltransferase 1/metabolism ; Diabetes Mellitus, Type 2/metabolism ; Diabetes Mellitus, Type 2/pathology ; Diabetes Mellitus, Type 2/virology ; Disease Models, Animal ; Enterovirus B, Human/metabolism ; Enterovirus B, Human/pathogenicity ; Female ; Gene Expression Regulation ; Glucose/metabolism ; Glucose/pharmacology ; Homeodomain Proteins/metabolism ; Humans ; Insulin-Secreting Cells/drug effects ; Insulin-Secreting Cells/metabolism ; Insulin-Secreting Cells/pathology ; Insulin-Secreting Cells/transplantation ; Male ; Mice ; Mice, Transgenic ; Procainamide/pharmacology ; Rats ; Repressor Proteins/metabolism ; Signal Transduction ; Trans-Activators/metabolism ; Transplantation, Heterologous
    • Abstract:
      Enteroviruses are suspected to contribute to insulin-producing β cell loss and hyperglycemia-induced diabetes. However, mechanisms are not fully defined. Here, we show that coxsackievirus B type 4 (CVB4) infection in human islet-engrafted mice and in rat insulinoma cells displays loss of unconventional prefoldin RPB5 interactor (URI) and PDX1, affecting β cell function and identity. Genetic URI ablation in the mouse pancreas causes PDX1 depletion in β cells. Importantly, diabetic PDX1 heterozygous mice overexpressing URI in β cells are more glucose tolerant. Mechanistically, URI loss triggers estrogen receptor nuclear translocation leading to DNA methyltransferase 1 (DNMT1) expression, which induces Pdx1 promoter hypermethylation and silencing. Consequently, demethylating agent procainamide-mediated DNMT1 inhibition reinstates PDX1 expression and protects against diabetes in pancreatic URI-depleted mice . Finally, the β cells of human diabetes patients show correlations between viral protein 1 and URI, PDX1, and DNMT1 levels. URI and DNMT1 expression and PDX1 silencing provide a causal link between enterovirus infection and diabetes.
      Competing Interests: The authors declare no competing interests.
      (© 2020 The Author(s).)
    • References:
      Virology. 2004 Nov 24;329(2):381-94. (PMID: 15518817)
      Biol Proced Online. 2009 Dec 03;11:3-31. (PMID: 19957062)
      N Engl J Med. 2020 Aug 20;383(8):789-790. (PMID: 32530585)
      Diabetol Metab Syndr. 2018 May 10;10:40. (PMID: 29760789)
      Cell Metab. 2014 Feb 4;19(2):259-71. (PMID: 24506867)
      Cell Metab. 2017 Mar 7;25(3):622-634. (PMID: 28215845)
      N Engl J Med. 1979 May 24;300(21):1173-9. (PMID: 219345)
      Proc Soc Exp Biol Med. 1955 Jan;88(1):22-4. (PMID: 14357332)
      Proc Natl Acad Sci U S A. 2007 Mar 20;104(12):5115-20. (PMID: 17360338)
      Acta Diabetol. 2010 Sep;47(3):193-9. (PMID: 19333547)
      Diabetologia. 1981 May;20(5):573-7. (PMID: 7026332)
      JCI Insight. 2018 Feb 8;3(3):. (PMID: 29415896)
      Nature. 2010 Apr 22;464(7292):1149-54. (PMID: 20364121)
      Cell Metab. 2014 May 6;19(5):872-82. (PMID: 24746806)
      Diabetes. 2009 Oct;58(10):2292-302. (PMID: 19587358)
      Pediatr Diabetes. 2012 Jun;13(4):334-9. (PMID: 22059423)
      J Biol Chem. 2017 Apr 7;292(14):5957-5969. (PMID: 28242761)
      Diabetes. 2015 Apr;64(4):1444-58. (PMID: 25377875)
      Dev Cell. 2013 Jul 15;26(1):3-7. (PMID: 23867225)
      Science. 2019 May 31;364(6443):. (PMID: 31147493)
      Cell Metab. 2019 Mar 5;29(3):755-768.e5. (PMID: 30713109)
      Cell Stem Cell. 2018 Jan 4;22(1):78-90.e4. (PMID: 29304344)
      Cell Metab. 2019 Mar 5;29(3):769-783.e4. (PMID: 30713110)
      Nat Genet. 2018 May;50(5):699-707. (PMID: 29662164)
      FEBS Lett. 2011 May 6;585(9):1269-75. (PMID: 21459093)
      Virology. 2008 Jun 5;375(2):480-91. (PMID: 18378272)
      Diabetes. 2015 Apr;64(4):1358-69. (PMID: 25392246)
      Science. 2003 Nov 14;302(5648):1208-12. (PMID: 14615539)
      J Clin Invest. 2008 Jun;118(6):2316-24. (PMID: 18464933)
      Cell Death Dis. 2016 Nov 3;7(11):e2452. (PMID: 27809303)
      Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):13525-13530. (PMID: 29203669)
      JCI Insight. 2018 Aug 9;3(15):. (PMID: 30089716)
      Sci Rep. 2019 Mar 6;9(1):3619. (PMID: 30842440)
      Cell Rep. 2017 Apr 18;19(3):584-600. (PMID: 28423321)
      Endocrinology. 2004 Feb;145(2):667-78. (PMID: 14592952)
      Nat Rev Endocrinol. 2019 Nov;15(11):635-650. (PMID: 31534209)
      Mol Cell. 2007 Oct 12;28(1):28-40. (PMID: 17936702)
      J Endocr Soc. 2017 Sep 11;1(10):1272-1286. (PMID: 29264452)
      Diabetologia. 2009 Jun;52(6):1143-51. (PMID: 19266182)
      Mol Cell Biol. 1997 Oct;17(10):6002-13. (PMID: 9315659)
      Physiol Behav. 2018 Apr 1;187:20-23. (PMID: 28843891)
      Cancer Cell. 2016 Jul 11;30(1):161-175. (PMID: 27411590)
      Biochem Biophys Res Commun. 2012 Oct 12;427(1):47-53. (PMID: 22975348)
      Cell Mol Life Sci. 2013 Nov;70(21):4169-80. (PMID: 23775130)
      Am J Physiol Gastrointest Liver Physiol. 2009 Dec;297(6):G1126-37. (PMID: 19808654)
      Diabetes Res Clin Pract. 2020 Jun;164:108166. (PMID: 32339533)
      Diabetologia. 2002 Mar;45(3):309-26. (PMID: 11914736)
      Diabetologia. 2019 May;62(5):744-753. (PMID: 30675626)
      Cancer Cell. 2016 Aug 8;30(2):290-307. (PMID: 27505673)
      J Biol Chem. 2005 Dec 9;280(49):40749-56. (PMID: 16230360)
      Trends Endocrinol Metab. 2013 Jul;24(7):324-31. (PMID: 23647931)
      BMJ. 2011 Feb 03;342:d35. (PMID: 21292721)
      Expert Rev Proteomics. 2013 Aug;10(4):365-80. (PMID: 23992419)
      J Clin Invest. 2010 Nov;120(11):4031-9. (PMID: 20978346)
      Curr Diabetes Rev. 2020;16(7):770-778. (PMID: 31544697)
      Diabetes. 2002 Dec;51 Suppl 3:S320-5. (PMID: 12475770)
      Nat Rev Endocrinol. 2010 May;6(5):279-89. (PMID: 20351698)
      Nature. 2014 Oct 23;514(7523):503-7. (PMID: 25141178)
      J Biol Chem. 2006 Feb 3;281(5):2649-53. (PMID: 16326700)
      Diabetes. 2013 Jul;62(7):2471-80. (PMID: 23569174)
      Genes Dev. 1998 Jun 15;12(12):1763-8. (PMID: 9637677)
      Genes Dev. 2011 Aug 15;25(16):1680-5. (PMID: 21852533)
      Cell. 2012 Sep 14;150(6):1223-34. (PMID: 22980982)
      Horm Res Paediatr. 2011;76 Suppl 1:57-64. (PMID: 21778751)
      Diabetes Metab Res Rev. 2017 Sep;33(6):. (PMID: 28303682)
      N Engl J Med. 2000 Feb 3;342(5):301-7. (PMID: 10655528)
      Nature. 1994 Dec 1;372(6505):425-32. (PMID: 7984236)
      Int J Oncol. 2013 Dec;43(6):2073-81. (PMID: 24141649)
      BMC Dev Biol. 2001;1:4. (PMID: 11299042)
      Cardiovasc Surg. 2003 Feb;11(1):12-8. (PMID: 12543566)
      Carcinogenesis. 2011 Jun;32(6):829-35. (PMID: 21362628)
      Diabetes. 2015 May;64(5):1682-7. (PMID: 25422108)
      Mol Endocrinol. 2012 Jul;26(7):1203-12. (PMID: 22570331)
      Viruses. 2019 Jul 02;11(7):. (PMID: 31269669)
      Dev Cell. 2015 Apr 6;33(1):67-81. (PMID: 25816988)
      Diabetes. 2002 Feb;51 Suppl 1:S138-43. (PMID: 11815473)
      J Clin Endocrinol Metab. 2000 Jan;85(1):432-40. (PMID: 10634421)
      J Clin Invest. 2013 Mar;123(3):1275-84. (PMID: 23434589)
      Diabetologia. 2014 Feb;57(2):392-401. (PMID: 24190581)
      Science. 2018 Mar 23;359(6382):1376-1383. (PMID: 29519916)
      Cancer Cell. 2014 Dec 8;26(6):826-839. (PMID: 25453901)
      J Clin Endocrinol Metab. 2016 Mar;101(3):1044-54. (PMID: 26713822)
      Nat Med. 2017 Apr;23(4):501-507. (PMID: 28263308)
      Oncotarget. 2017 Feb 21;8(8):12620-12636. (PMID: 28147344)
      Bioinformatics. 2005 Nov 1;21(21):4067-8. (PMID: 16141249)
      Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12236-41. (PMID: 12221286)
      J Diabetes Complications. 2001 Nov-Dec;15(6):328-35. (PMID: 11711327)
    • Grant Information:
      R01 AI116920 United States AI NIAID NIH HHS
    • Contributed Indexing:
      Keywords: DNMT1; PDX1; beta cells; coxsackievirus B Type 4; diabetes; enteroviruses; estrogen receptor; hypermethylation; prefoldin URI; transdifferentiation
    • Accession Number:
      0 (Capsid Proteins)
      0 (Homeodomain Proteins)
      0 (Repressor Proteins)
      0 (Trans-Activators)
      0 (Uri1 protein, mouse)
      0 (VP1 protein, enterovirus B)
      0 (pancreatic and duodenal homeobox 1 protein)
      EC 2.1.1.37 (DNA (Cytosine-5-)-Methyltransferase 1)
      EC 2.1.1.37 (Dnmt1 protein, mouse)
      IY9XDZ35W2 (Glucose)
      L39WTC366D (Procainamide)
    • Subject Terms:
      Maturity-Onset Diabetes of the Young, Type 4
    • Publication Date:
      Date Created: 20201118 Date Completed: 20220225 Latest Revision: 20220225
    • Publication Date:
      20240829
    • Accession Number:
      PMC7659558
    • Accession Number:
      10.1016/j.xcrm.2020.100125
    • Accession Number:
      33205075